Unique Signatures of Highly Constrained Genes Across Publicly Available Genomic Databases

Publicly available genomic databases and genetic constraint scores are crucial in understanding human population variation and the identification of variants that are likely to have a deleterious impact causing human disease. We utilized the one of largest publicly available databases, gnomAD, to determine genes that are highly constrained for only LoF, only missense, and both LoF/missense variants, identified their unique signatures, and explored their causal relationship with human conditions. Those genes were evaluated for unique patterns including their chromosomal location, tissue level expression, gene ontology analysis, and gene family categorization using multiple publicly available databases. Those highly constrained genes associated with human disease, we identified unique patterns of inheritance, protein size, and enrichment in distinct molecular pathways. In addition, we identified a cohort of highly constrained genes that are currently not known to cause human disease, that we suggest will be candidates to pursue as novel disease-associated genes. In summary, these insights not only elucidate biological pathways of highly constrained genes that expand our understanding of critical cellular proteins but also advance research in rare diseases.Publicly available genomic databases and genetic constraint scores are crucial in understanding human population variation and the identification of variants that are likely to have a deleterious impact causing human disease. We utilized the one of largest publicly available databases, gnomAD, to determine genes that are highly constrained for only LoF, only missense, and both LoF/missense variants, identified their unique signatures, and explored their causal relationship with human conditions. Those genes were evaluated for unique patterns including their chromosomal location, tissue level expression, gene ontology analysis, and gene family categorization using multiple publicly available databases. Those highly constrained genes associated with human disease, we identified unique patterns of inheritance, protein size, and enrichment in distinct molecular pathways. In addition, we identified a cohort of highly constrained genes that are currently not known to cause human disease, that we suggest will be candidates to pursue as novel disease-associated genes. In summary, these insights not only elucidate biological pathways of highly constrained genes that expand our understanding of critical cellular proteins but also advance research in rare diseases

Cancer Progression in Retinoblastoma: Chemoresistance and BCOR

Retinoblastoma is the most common pediatric eye cancer with 8000 new diagnoses worldwide each year. Although treatment strategies have significantly improved over the past few decades, severe post-treatment ocular complications and limited pharmacological options as secondary treatment emphasize the need for therapeutic discovery. The most significant barrier to this is our gap in knowledge regarding mechanisms underlying retinoblastoma cancer progression. Our objective is to shed insight into two major contributors to tumor progression: chemoresistance and BCOR loss. Here, we demonstrate repeated sublethal exposure of retinoblastoma to the widely used chemotherapy agent carboplatin results in generalized induction of transcriptomic reprogramming involving the PI3K-AKT pathway, ABC transporters, and metabolic regulators. We also propose a multi-faceted role for BCOR in retinoblastoma involving cell cycle and hypoxia. Altogether, these investigations provide a deeper understanding of mechanisms underlying retinoblastoma cancer progression and serve as a stepping-stone for downstream therapeutic discovery to improve patient care.</p

Tumor cell-intrinsic p38 MAPK signaling promotes IL1⍺-mediated stromal inflammation and therapeutic resistance in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a KRAS-driven inflammatory program and a desmoplastic stroma, which contribute to the profoundly chemoresistant phenotype. The tumor stroma contains an abundance of cancer-associated fibroblasts (CAFs), which engage in extensive paracrine crosstalk with tumor cells to perpetuate pro-tumorigenic inflammation. Interleukin-1α (IL1α), a pleiotropic, tumor cell-derived cytokine, plays a critical role in shaping the stromal landscape. To provide insights into the molecular mechanisms regulating IL1A expression in PDAC, we performed transcriptional profiling of TCGA datasets and pharmacologic screening in PDAC cells and identified p38α MAPK as a key positive regulator of IL1A expression. Both genetic and pharmacologic inhibition of p38 MAPK significantly diminished IL1α production in vitro. Chromatin- and co-immunoprecipitation analyses revealed that p38 MAPK coordinates the transcription factors Sp1 and the p65 subunit of NFκB to drive IL1A overexpression. Single-cell RNA-sequencing of a highly desmoplastic murine PDAC model, Ptf1aCre/+; LSL-KrasG12D/+; Tgfbr2flox/flox (PKT), confirmed that p38 MAPK inhibition significantly decreases tumor cell-derived Il1a and attenuates the inflammatory CAF phenotype in a paracrine IL1α-dependent manner. Furthermore, p38 MAPK inhibition favorably modulated intratumoral immunosuppressive myeloid populations and augmented chemotherapeutic efficacy to substantially reduce tumor burden and improve overall survival in PKT mice. These findings illustrate a cellular mechanism of tumor cell-intrinsic p38-p65/Sp1-IL1α signaling that is responsible for sustaining stromal inflammation and CAF activation, offering an attractive therapeutic approach to enhance chemosensitivity in PDAC

Isolating neural signatures of conscious speech perception with a no-report sine-wave speech paradigm

Identifying neural correlates of conscious perception is a fundamental endeavor of cognitive neuroscience. Most studies so far have focused on visual awareness along with trial-by-trial reports of task relevant stimuli, which can confound neural measures of perceptual awareness with post-perceptual processing. Here, we used a three-phase sine-wave speech paradigm that dissociated between conscious speech perception and task relevance while recording EEG in humans of both sexes. Compared to tokens perceived as noise, physically identical sine-wave speech tokens that were perceived as speech elicited a left-lateralized, near-vertex negativity, which we interpret as a phonological version of a perceptual awareness negativity. This response appeared between 200 and 300 ms after token onset and was not present for frequency-flipped control tokens that were never perceived as speech. In contrast, the P3b elicited by task-irrelevant tokens did not significantly differ when the tokens were perceived as speech versus noise, and was only enhanced for tokens that were both perceived as speechrelevant to the task. Our results extend the findings from previous studies on visual awareness and speech perception, and suggest that correlates of conscious perception, across types of conscious content, are most likely to be found in mid-latency negative-going brain responses in content-specific sensory areas.How patterns of brain activity give rise to conscious perception is a fundamental question of cognitive neuroscience. Here, we asked whether markers of conscious speech perception can be separated from task-related confounds. We combined sine-wave speech - a degraded speech signal that is heard as noise by naive individuals but can readily be heard as speech after minimal training - with a no-report paradigm that independently manipulated perception (speech versus non-speech) and task (relevant versus irrelevant). Using this paradigm, we were able to identify a marker of speech perception in mid-latency responses over left frontotemporal EEG channels that was independent of task. Our results demonstrate that the "perceptual awareness negativity" is present for a new type of perceptual content (speech)

Repeat thrombectomy after large vessel re-occlusion: a propensity score matched analysis of technical and clinical outcomes

Endovascular thrombectomy (EVT) remains the standard of care for acute large vessel occlusion (LVO) stroke. However, the safety and efficacy of repeat thrombectomy (rEVT) in recurrent LVO remains unclear. This study uses a large real-world patient cohort to study technical and clinical outcomes after rEVT. This is a retrospective cohort study including patients who underwent thrombectomy between January 2013 and December 2022. Data were included from 21 comprehensive stroke centers globally through the Stroke Thrombectomy and Aneurysm Registry (STAR). Patients undergoing single EVT or rEVT within 30 days of LVO stroke were included in the study. Propensity score matching was used to compare patients undergoing single EVT versus rEVT. Out of a total of 7387 patients who underwent thrombectomy for LVO stroke, 90 (1.2%) patients underwent rEVT for the same vascular territory within 30 days. The median (IQR) time to re-occlusion was 2 (1-7) days. Compared with a matched cohort of patients undergoing a single EVT procedure, patients undergoing rEVT had a comparable rate of good functional outcome and mortality rate, but a higher rate of symptomatic intracranial hemorrhage (sICH). There was a significant reduction in the National Institutes of Health Stroke Scale (NIHSS) score of patients who underwent rEVT at discharge compared with baseline (-4.8±11.4; P=0.006). The rate of successful recanalization was similar in the single thrombectomy and rEVT groups (78% vs 80%, P=0.171) and between index and rEVT performed on the same patient (79% vs 80%; P=0.593). Short-interval rEVT is associated with an improvement in the NIHSS score following large vessel re-occlusion. Compared with single thrombectomy, there was a higher rate of sICH with rEVT, but without a significant impact on rates of functional independence or mortality

Carbon dioxide as an indicator of bioaerosol activity and human health in K-12 school systems: a scoping review of current knowledge

Abstract Indoor Air Quality (IAQ) in schools has received attention over the past decades but still lacks specific standards and regulations. This study aimed to review the impact of bioaerosol activity in indoor environments on acute respiratory diseases and explore whether carbon dioxide can be used as an indicator of bioaerosol and respiratory diseases in indoor environments in K-12 school systems. Findings suggest a lack of a consensual approach to evaluate bioaerosols impacting IAQ in indoor infrastructures, particularly in school environments; an elevated CO2 concentration inside the school classrooms was not uncommon, and the evidence of unsatisfactory and degraded IAQ (surpassing ASHRAE standards) at public schools in rural and urban settings in one of the North Central County, Florida. It was found that CO2 levels can be associated with bioaerosol activity, and sufficient ventilation within the space substantially reduces the airborne time of respiratory droplets and CO2 levels. CO2 monitoring can act as an effective, low-cost alternative to surveying or detecting the prevalence of respiratory diseases, which may hold strength through establishing critical CO2 thresholds and, thereafter associating it with the infectious doses of pathogen activity